ESPEYB17 5. Bone, Growth Plate and Mineral Metabolism Novel Receptor Signaling Mechanisms (2 abstracts)
5.10. Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodelling
Nishimori S , O’Meara MJ , Castro CD , Noda H , Cetinbas M , da Silva Martins J , Ayturk U , Brooks DJ , Bruce M , Nagata M , Ono W , Janton CJ , Bouxsein ML , Foretz M , Berdeaux R , Sadreyev RI , Gardella T , Jüppner H , Kronenberg HM & Wein MN
Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
To read the full abstract: J Clin Invest 2019;129:5187–5203.
In brief: This report establishes inhibition of salt-inducible kinases as a central mechanism by which the parathyroid hormone 1 receptor (PTH1R) exerts its effects in both growth plate chondrocytes and osteoblasts/osteocytes during skeletal development, growth, and remodelling.
Commentary: The parathyroid hormone 1 receptor (PTH1R) is a G protein-coupled receptor that is critical for mineral homeostasis, but also for skeletal development, growth and bone metabolism. Its importance in skeletal development was first indicated by the finding that Jansen type metaphyseal chondrodysplasia, characterized by severe short stature, short bowed limbs, and hypercalcemia and hypophosphatemia despite the lack of parathyroid abnormalities, is caused by activating mutations in PTH1R (Ref PubMed: 7701349) and later that biallelic inactivating mutations causes Blomstrands lethal chondrodysplasia (PubMed: 9649554), characterized by short limbs, hydrops fetalis, increased bone density, and advanced skeletal maturation. Mouse studies have detailed the cellular mechanism by which PTH1R signalling regulates growth plate chondrogenesis and bone metabolism, and recombinant PTH is now used clinically as a treatment for both osteoporosis and hypoparathyroidism. It is well established that PTH1R signalling leads to accumulation of cAMP. However, understanding of the downstream signaling of PTH1R remains incomplete.
The current article sheds new light on the downstream signalling mechanism of Pth1r. The authors demonstrated that salt-inducible kinase 3 (Sik3), assisted by Sik1, and -2, drives hypertrophy of growth plate chondrocytes and that a large part of the effect of Pth1r signalling is due to its inhibitory effects on Sik3 and other Sik proteins. Consequently, deletion of Sik3 rescued the lethal phenotype caused by chondrocyte hypertrophy and mineralization in homozygous Pthrp knockout mice. Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes caused high bone mass with accelerated bone turnover, mimicking the high-turnover phenotype in mice with constitutive Pth1r activation in these cells. Furthermore, the data indicated that class IIa histone deacetylases (e.g., HDAC4) are downstream mediators of Sik action in growth plate and osteoblasts/osteocytes.
Taken together, the presented data establish Sik inhibition as a central mechanism in Pth1r action on skeletal development and metabolism and suggest that cAMP-regulated Sik activity is a key mechanism mediating the action of G protein-coupled receptors.
Volume 17
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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